title: PPARα and fatty acid oxidation mediate glucocorticoid resistance in chronic lymphocytic leukemia.
abstract: High-dose glucocorticoids (GCs) can be a useful treatment for aggressive forms of chronic lymphocytic leukemia (CLL). However, their mechanism of action is not well understood, and resistance to GCs is inevitable. In a minimal, serum-free culture system, the synthetic GC dexamethasone (DEX) was found to decrease the metabolic activity of CLL cells, indicated by down-regulation of pyruvate kinase M2 (PKM2) expression and activity, decreased levels of pyruvate and its metabolites, and loss of mitochondrial membrane potential. This metabolic restriction was associated with decreased size and death of some of the tumor cells in the population. Concomitant plasma membrane damage increased killing of CLL cells by DEX. However, the nuclear receptor peroxisome proliferator activated receptor α (PPARα), which regulates fatty acid oxidation, was also increased by DEX, and adipocyte-derived lipids, lipoproteins, and propionic acid protected CLL cells from DEX. PPARα and fatty acid oxidation enzyme inhibitors increased DEX-mediated killing of CLL cells in vitro and clearance of CLL xenografts in vivo. These findings suggest that GCs prevent tumor cells from generating the energy needed to repair membrane damage, fatty acid oxidation is a mechanism of resistance to GC-mediated cytotoxicity, and PPARα inhibition is a strategy to improve the therapeutic efficacy of GCs.
authors.affiliation: Division of Molecular and Cellular Biology, Sunnybrook Research Institute, 2075 Bayview Ave., Toronto, ON, Canada.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Tung
authors.forename: Yonghong
authors.initials: Y
authors.lastname: Shi
authors.forename: Karry
authors.initials: K
authors.lastname: Wong
authors.forename: Fang
authors.initials: F
authors.lastname: Zhu
authors.forename: Reg
authors.initials: R
authors.lastname: Gorczynski
authors.forename: Robert C
authors.initials: RC
authors.lastname: Laister
authors.forename: Mark
authors.initials: M
authors.lastname: Minden
authors.forename: Anne-Kareen
authors.initials: AK
authors.lastname: Blechert
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Genzel
authors.forename: Udo
authors.initials: U
authors.lastname: Reichl
authors.forename: David E
authors.initials: DE
authors.lastname: Spaner
mesh_terms: D017667:Adipocytes / Q000166:cytology; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D017077:Culture Media, Conditioned; D003907:Dexamethasone / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D005227:Fatty Acids / Q000378:metabolism*; D015973:Gene Expression Regulation, Leukemic; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy / Q000378:metabolism*; D050356:Lipid Metabolism; D053078:Membrane Potential, Mitochondrial; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D010100:Oxygen / Q000378:metabolism; D047493:PPAR alpha / Q000378:metabolism*; D010766:Phosphorylation; D011422:Propionates / Q000737:chemistry; D013963:Thyroid Hormones / Q000378:metabolism; D000097810:Thyroid Hormone-Binding Proteins
chemical_list: D002352:Carrier Proteins; D017077:Culture Media, Conditioned; D003907:Dexamethasone; D005227:Fatty Acids; D005938:Glucocorticoids; D008565:Membrane Proteins; D010100:Oxygen; D047493:PPAR alpha; D011422:Propionates; D013963:Thyroid Hormones; D000097810:Thyroid Hormone-Binding Proteins; C029658:propionic acid